Target Validation, 2010

Objective/Rationale:
A growing body of evidence suggests that iron dysregulation may contribute to neurodegeneration associated with Parkinson’s disease (PD). Recent work from our laboratory suggests that this may be in part due to activation of an iron-requiring family of enzymes known as prolyl hydroxylases (PHDs). These enzymes act to reduce levels of various transcription factors involved in up-regulation of a host of neuroprotective genes. We propose to establish whether PHD inhibition is a viable therapeutic target for development of novel treatments to combat PD.

Project Description:
We will test the ability of pharmacological general PHD inhibition to prevent iron and redox dysregulation, mitochondrial dysfunction and midbrain dopaminergic cell loss associated with a chronic, age-related pre-clinical model of PD recently established by our laboratory, inducible dopaminergic glutathione depletion (Chinta et al., JNS 2007). This will be performed in conjunction with pharmokinetic/pharmodynamic studies in order to estimate maximal drug bioavailability. Testing the neuroprotective affects of PHD inhibition in this model will allow us to assess the potential involvement of PHDs in neurodegeneration in a system that emulates the chronic and multifactoral nature of the human disorder.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Elevated iron levels are believed to contribute to neuronal cell loss associated with PD. However, given that iron is an important co-factor for several vital cellular functions, iron chelation is unlikely to be of practival use as a therapeutic intervention for the disorder. A better mechanistic understanding of the role of iron dysregulation in PD would allow development of more selective therapies that could eliminate unwanted side effects associated with general iron chelation.

Anticipated Outcome:
The proposed research will not only allow us to assess the potential for PHD inhibition as a novel therapeutic target for the disorder but will also allow us to establish a more accurate animal model for future testing of potential small molecule and/or selective PHD inhibitors in vivo.

FINAL OUTCOME

We performed pharmokinetic/pharmodynamic studies in order to determine the optimal drug delivery dosage regimin in older or younger pre-clinical models for the general prolyl hydroxylase (PHD) inhibitor 3,4-dihydroxybenzoate (DHB). This information guided our decisions regarding dosage in an age-related chronic PD pre-clinical model (inducible glutathione depletion, Chinta et al., 2007). Results indicated that in older pre-clinical models (where neurodegenerative effects are first observed), treatment with DHB at one particular dose, with assessment after 14 days, prevented iron dysregulation and resulted in significant retention of both mitochondrial respiratory function and nigral dopaminergic cell numbers versus saline-treated controls. These data suggest that at this dosage, DHB administration in a chronic, age-related model of the disorder results in neuroprotection similar to those previously observed in the more acute MPTP intoxication model (Lee et al., 2009).